The theme of this project is that actual measurement of forces between large molecules will teach us how these molecules interact to form the functioning units of a living cell. The results of these direct measurements are quite different from earlier expectation. For example, we have learned that in the important last few nanometers where molecules approach contact, interaction is dominated by a continuously varying work of removal of water solvent from their surfaces, between phospholipid bilayer membranes, these important "hydration forces" are exquisitely sensitive to very small changes ln the composition of the lipid polar groups, changes that are under the biochemical control after formation of the membrane structure. We have recently succeeded in measuring not only the force vs. separation of molecules but also the change in their thermal motion during mutual approach. Outside the 1 nanometer range of direct hydration repulsion it appears that macromolecules move or undulate to repel by the "steric" action of molecules colliding. However these collisions never involve molecular contact but rather occur through long-range forces between molecular surfaces. The result is a form of interaction qualitively different from any that has been assumed to be responsible for molecular assembly. One can now use these data to see how the measured forces act at the functional level of, say, controlling the contact and fusion of membranes as in a secretory process, or determining the packing of DNA or other long molecules, or perturbing the rearrangements of protein structure that effect the "gating" of trans-membrane ionic channels, or even affect the activity of enzymes whose function depends on particular forms of packing components. We have been carrying out work on each of these processes.